2-cycloalkylmethylamino-benzhydrols and benzophenones



United States Patent Ofifice Patented Nov. 8, 1966 This application is adivisional application of Serial No. 262,221, filed March 1, 1963, nowUS. Pat. No. 3,192,199.

This invention relates to a new and novel process for the production ofsubstituted 1,4-benzodiazepines of the formula:

wherein R represents a cycloalkylmethyl group such as cyclopropylmethyl,cyclobutylmethyl or cyclopentylmethyl and R represents hydrogen, loweralkyl, lower alkoxy or halogen such as chlorine or bromine.

This invention also relates to certain novel intermediates obtainedduring the process.

The compounds of the above formula are useful as tranquilizers. Forexample, they exhibit anti-anxiety and sedative activity withoutundesirable side-effects such as hypnosis. In addition, they are usefulas intermediates for the production of other substitutedbenzodiazepines.

In accordance with our invention, these substituted 1,4-benzodiazepinesare prepared by the following sequence of steps.

Step I of our novel process comprises treating a 2-amino-halobenzophenone such as Z-amino-S-chlorobenzophenone:

dissolved in a mixture of tetrahydrofuran and triethylamine with anequal molar ratio of the desired cycloalkanecarboxylic acid chloridesuch as, for example, cyclopropanecarboxylic acid chloride, followed byrefluxing the resulting reaction mixture to yield a2-cyclopropylcarbonylamido-S-chlorobenzophenone of the formula:

The above reaction product can be readily separated from the motherliquor by the removal of the solvents.

Step II comprises reducing the compound obtained in accordance with StepI with an excess of a reducing agent such as lithium aluminum hydridefollowed by aqueous hydrolysis to form the corresponding2-cycloalkylmethylaminohalobenzhydrol such as, for example,2-cyclopropylmethylamino-S-chlorobenzhydrol having the followingstructural formula:

Cl OHOH Step III comprises oxidizing the benzhy-drol group of theproduct of Step II with an excess of manganese dioxide to yield, forexample, 2-cyclopropylmethylamino-5- chlorobenzophenone of the formula:

Step IV comprises the preparation of a phthalimidoacetyl derivative ofthe product obtained in accordance with Step III. For example,2-(N-phthalimidoacetyl-N- cyclopropylmethyl)-amino-5-chlorobenzophenoneof the formula:

may be prepared by refluxing one mole of2-cyclopr-opylmethylamino-5-chlorobenzophenone (obtained in Step III) intetrahydrofuran with two moles of phthalimidoacetyl chloride. Thereaction product is readily obtained by removal of the solvent.

Step V, the fin al step, comprises the ring closure with hydrazinehydrate of the phthalimidoacetyl derivatives obtained in accordance withStep IV thus forming the novel compounds of this invention. Thus, forexample, when a solution of2-(N-phthalimidoacetyl-N-cyclopropylmethyl)-amino-5-chlorobenzophenonein a mixture of chloroform and ethanol is reacted with an excess ofhydrazine hydrate to give a compound of the formula:

CH -A; I o C Example I.2-eyelopr0pylcarbonylamid0-5-chl0r0- benzophenoneTo 400.5 g. (1.73 moles) of 2-amino-5-chlorobenzophenone dissolved in220 g. (2.18 moles) of triethylamine and 3.5 liters of tetrahydrofuranis added cautiously 181 'g. (1.73 moles) of cyclopropanecarboxylic acidchloride.

The reaction is refluxed 2 /2 hours and allowed to cool to roomtemperature. The solvent is then removed under vacuum to obtain2-cycl-opropylcarbonylamid0-5-chl0robenzophenone as a residue which isdissolved in 1 liter of methylene chloride, washed twice with 5%hydrochloric acid, and then twice with potassium hydroxide. Themethylene chloride solution is then dried over anhydrous magnesiumsulfate, filtered and the solvent removed under vacuum. The residue isrecrystallized from 1500 ml. of methanol, charcoaling the hot solutionto give 356 g. of 2-cyclopr0pylcarbonylamido-S-chlorobenzophenone, M.P.105 105.5 C. (69% yield), containing in the infrared a single unresolvedcarbonyl band at 1670 cm.-

Example 2.-2-cyel0propylmethylamin0-5-chl0r0benzhydrol To a slurry of94.8 g. (2.47 moles) of lithium aluminum hydride in 1.2 liters oftetrahydrofuran is added with stirring a solution of 356 g. (1.18 moles)of 2-cyclopropyl-carbonyl-amido-S-chlorobenzophenone in 1.8 liters oftetrahydrofuran. The addition takes place 80 minutes while maintaininggentle refluxing, and the reaction mixture is then refluxed overnightand allowed to cool to room temperature over a period of 3 days. Thecomplex formed in the reaction mixture is then hydrolyzed with water.During the hydrolysis, 500 milliliters of tetrahydrofuran is added tofacilitate stirring. At a point where the flocc-ulant white precipitatesettles quickly when stirring is interrupted, the mixture is filtered,the filter cake washed with solvent, the combined filtrates dried overmagnesium sulfate, filtered and the solvent removed under vacuum toobtain 2-cyclopropylmethylarnino-5-chlorobenzhydrol as a residue. Theresidue is recrystallized tfrom 1300 ml. of Skelly B, giving 315 g. of2-cyclopropylmethylamino-S-chlorobenzhydrol, M.P. 85-855 C. (93% yield).

methylamino-S-chlorobenzhydrol in 4 liters of benzene is added 453.6 g.(5.22 moles) of manganese dioxide, freshly prepared according to themethod of Attenburrow et al., J.C.S. 1952, 1104. The mixture is thenrefluxed for 1% hours, filtered, and the filtrate evaporated undervacuum. The reddish residue is recrystallized from 510 ml. ofacetone-10% water, giving 181 g. of pure2-cyclopropylmethylamine-5-chlorobenzophenone, M.P. 79-80 C. (58%yield.) Upon concentration of the mother liquor a second crop of2-cyclopropylmethylamino-5- chlorobenzophenone weighing 34.1 g. andmelting at 76.5 7 8 C. are obtained.

Analysis.Calcd: C, 71.45; H, 5.64; Cl, 12.41. Found: C, 71.67; H, 5.82;Cl, 12.68; 12.71.

Example 4.Preparati0n of 2(N-phthalimidoacetyl-N- cyclopropylmethyl)-amin0-5-ehlorobenzophenone To a solution of 36.0 g. (0.126 mole) of2-cyclopropylmethylamino-S-chlor-obenzophenone in 500 ml. oftetrahydrofuran is added 50.7 g. (0.252 mole) of phthalimidoacetylchloride. The resulting solution is refluxed for 16 to 24 hours, thesolvent removed under vacuum, the residual oil crystallized from 200 ml.of ethanol and recrystallized from 500 ml. of 80% ethanol-20%tetrahydrofuran giving 44.7 g. of 2(N-phthalimidoacetyl-N-cyclopropylmethyl)-amino-5 chlorobenzophenone, M.P. 163164 C. (75%yield.)

Analysis.-Calcd: C, 68.57; H, 4.48; N, 5.92. Found: C, 68.36; H, 4.29;N, 5.85.

Example 5 .Preparation of 1 -cyclopr0py [methyl-5-phenyl-7-chl0r0-1H-1,4-benz0diazepine-2 (3H) one To a solution of 39.5g. (0.0845 mole) of 2(N-phthalimidoacetyl-N-cyclopropylmethyl)amino-5chlorobenzophenone in a mixture of 423 ml. of chloroform and 423 ml. ofethanol is added 9.52 g. (0.1903 mole) of hydrazine hydrate and 9.52 ml.of water. This solution is allowed to stand at room temperature. Inthree hours a precipitate begins to form in the solution. After standing16 to 24 hours a voluminous pulpy white precipitate forms. The solventsare removed under vacuum while keeping the temperature under 40 C. andthe residue is partitioned between dilute ammonia water and ether. Theaqueous layer is separated and washed with ether, the ether extractedwith 5% hydrochloric acid, the acidic solution is made basic with 10%sodium hydroxide and again extracted with ether. Since some spontaneouscrystallization occurs in the ether, the solvent is removed withoutdrying under vacuum and the residue is recrystallized from 35 ml. ofethanol giving 18.0 ofl-cyclopropylmethyl-S-phenyl-7-chloro-1H-1,4-benzodiazepine 2(3H) one,M.P. 146 C. (65% yield.)

Analysis.Calc"d: C, 70.25; H, 5.28; H, 8.62. Found: C, 70.35; H, 5.41;H, 8.42.

It is understood that the foregoing detailed description is given merelyby way of illustration and that many variations may be made thereinwithout departing from the spirit of our invention.

Having described our invention, what we desire to secure by LettersPatent is:

We claim:

1. A compound of the formula:

in which R is a member selected from the group consisting ofcyclopropylmethyl, cyclobutylmethyl and cyclopentylmet'hyl and R is amember of the group consisting of hydrogen, chlorine, bromine, loweralkyl and lower alkoxy.

5 6 2. Z-cyclopropylmethylamino-5-ch1orobenzophenone. References Citedby the Examiner 3. A compound of the formula: UNITED STATES PATENTS R,2,993,062 7/1961 Moyle et a1. 260562 g 5 3,152,179 10/1964 Garland260--570.5 X B2 3,153,093 10/1964 Horrom et a1 260570.5

CHOH OTHER REFERENCES Fischer et a1.: German Auslegeschrift 1,005,784(K1 451 5), 2 pages spec.

Larsson, Chemical Abstracts, vol. 45, page 1494 (1951).

Turner, Jour. American Chemical Society, vol. 76, in which R is a memberselected from the group conpages 5 75 954 sisting of cyclopropylmethyl,cyclobutylmethyl and cyclopentylmethyl and R is a membercf the groupconsist- 15 CHARLES B, PARKER, Primary Examiner, iggvelefanlgirlogen,chlorine, bromine, lower alkyl and JOHN D. RANDOLPH Examiner.

4. 2-cyc1opropylmethylamino-5-chlorobenzhydrol. N. TROUSOF, R. V. HINES,Assistant Examiner.

1. A COMPOUND OF THE FORMULA: 1-(R1-NH-),2-(PHENYL-CO-),R2-BENZENE INWHICH R1 IS A MEMBER SELECTED FROM THE GROUP CONSISTING OFCYCLOPROPYLMETHYL, CYCLOBUTYLMETHYL AND CYCLOPENTYLMETHYL AND R2 IS AMEMBER OF THE GROUP CONSISTING OF HYDROGEN, CHLORINE, BROMINE, LOWERALKYL AND LOWER ALKOXY.